Method for the manufacture of pressure sensitive adhesives

ABSTRACT

A method for the manufacture of an adhesive id described, comprising: (A) Providing an initial reaction product of a solution polymerization reaction, the initial reaction product comprising polymer, unreacted polymerizable reactant, non-poly-merizable material, and solvent; and (B) Purifying the initial reaction product by adding an oxidizing agent and a reducing agent to the initial reaction product and allowing the unreacted polymerizable reactant in the initial reaction product to further react, thereby providing a second reaction product comprising additional polymer and a lower level of unreacted polymerizable reactant than was present in the initial reaction product. Optionally, the method of the invention may further comprise: Precipitating the polymer from the second reaction product to provide a precipitated polymer, and separating the precipitated polymer from the remainder of the second reaction product, the precipitated polymer comprising a lower level of non-polymerizable material or unreacted polymerizable reactant or both non-polymerizable material and unreacted polymerizable reactant than was present in the second reaction product.

The present invention relates to a method for the manufacture of anadhesive having low concentrations of residual components.

BACKGROUND OF THE INVENTION

Adhesive compositions including one or more polymers are often used inthe manufacture of medical products that are designed for use in contactwith human skin. Adhesive wound dressings may include components tocover a wound, absorb fluids and/or deliver medicaments to the injuredskin. Such dressings typically include an adhesive backing which may beapplied directly to the skin to maintain the dressing in place over theinjury. Additionally, transdermal patches have become an accepted meansfor the delivery of certain molecules through the layers of the skin,thus eliminating the need for injections. Transdermal patches include adrug dosage which may be stored in an appropriate medium and affixed toan adhesive coated backing. The backing on the transdermal patch isintended to be adhesively affixed to an area of human skin to place andhold the drug-carrying medium in direct contact with the skin andthereby promote the delivery of the drug through the skin. In someinstances, the drug dosage may be directly incorporated into theadhesive used to secure the patch to the skin. Adhesive compositionsused for securing medical products to human skin are preferably free ofsignificant concentrations of unreacted materials such as residualmonomer components, initiator materials, inhibitors or other agents. Inaddition to enhancing the adhesion, cohesion, stretch and/or adhesivetack of the adhesive, a low level of significant impurities in suchadhesive formulations is also desired to avoid certain unwanted featuresin the final product, such as unpleasant odors or the like.

Adhesive polymers that have been prepared by conventional free radicalsolution polymerization generally include impurities, such as residualmonomers, initiator materials, inhibitors or other agents. Althoughresidual monomers may be removed from the adhesive polymer by use ofscavenger (or scavenging) monomers, this method also requires theremoval of the scavenger monomer and the polymers that result aregenerally not the same as the original adhesive polymer obtained duringthe primary polymerization reaction. Alternatively, impurities remainingafter free radical solution polymerization may also be removed bymultiple heating and evaporation steps which remove volatile components.But, this method may crosslink, gel or degrade the polymer and it istime consuming, costly, and relies upon the volatility of anyimpurities.

There is a need to provide clean, adhesive polymers prepared by freeradical solution polymerization and to improve the ability to removeimpurities from such adhesive polymers.

SUMMARY OF THE INVENTION

The invention provides a method for the manufacture of an adhesive. Insome embodiments, the invention provides a method, comprising:

(A) Providing an initial reaction product of a solution polymerizationreaction, the initial reaction product comprising polymer, unreactedpolymerizable reactant, non-polymerizable material, and solvent; and

(B) Purifying the initial reaction product by adding an oxidizing agentand a reducing agent to the initial reaction product and allowing theunreacted polymerizable reactant in the initial reaction product tofurther react, thereby providing a second reaction product comprisingadditional polymer and a lower level of unreacted polymerizable reactantthan was present in the initial reaction product.

In another embodiment, the invention provides a method as defined aboveand further comprising the steps of

(C) Precipitating the polymer from the second reaction product toprovide a precipitated polymer; and

(D) Separating the precipitated polymer from the remainder of the secondreaction product, the precipitated polymer comprising a lower level ofnon-polymerizable material or unreacted polymerizable reactant or bothnon-polymerizable material and unreacted polymerizable reactant than waspresent in the second reaction product.

In still another embodiment, the invention provides a method for themanufacture of an adhesive, comprising:

(A) Providing an initial reaction product of a solution polymerizationreaction, the initial reaction product comprising a copolymer ofisooctyl acrylate and acrylamide, unreacted polymerizable reactant,non-polymerizable material, and solvent;

(B) Purifying the initial reaction product by adding an oxidizing agentand a reducing agent to the initial reaction product and allowing theunreacted polymerizable reactant in the initial reaction product tofurther react, thereby providing a second reaction product comprisingadditional polymer and a lower level of unreacted polymerizable reactantthan was present in the initial reaction product; and

(C) Precipitating the non-polymerizable material from the reactionproduct to provide a purified copolymer of isooctyl acrylate andacrylamide comprising less than about 200 ppm of unreacted isooctylacrylate or acrylamide.

In one embodiment, the amount of acrylamide in the purified copolymerwill be below the limit of detection.

The invention will be further understood by those skilled in the artupon consideration of the remainder of the disclosure, including theDetailed Description of the Preferred Embodiment and the appendedclaims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The invention provides a process for the manufacture of solutionpolymerized polymers suitable for use as a medical adhesive. In oneembodiment, the process of the invention provides acrylate copolymershaving a reduced content of undesired reactant materials includingreduced levels of unreacted polymerizable reactant material (e.g.,monomers) as well as a reduced levels of non-polymerizable material.

As described herein, acrylate (or methacrylate) polymers of theinvention are copolymers of a primary, alkyl acrylate (or alkylmethacrylate), monomer and an optional polar comonomer.

The primary, alkyl acrylate (or alkyl methacrylate), monomer or monomersof the above-defined acrylate (or methacrylate) polymer are selected toprovide a tacky or tackifiable material upon polymerization.Representative examples of primary monomers which may be used incombination are alkyl acrylates, such as isooctyl, 2-ethylhexyl,n-butyl, ethyl, methyl, and dimethylhexyl, and alkyl methacrylates, suchas lauryl, isodecyl, and tridecyl. In certain embodiments, the primaryacrylate monomer will comprise a C₄-C₁₂ acrylic ester such as thoseselected from the group: isooctyl acrylate (“IOA”), 2-ethylhexylacrylate, 2-methyl butyl acrylate, and butyl acrylate as well ascombinations of two or more of the foregoing.

The adhesive compositions provided according to the invention generallycomprise an acrylate (or methacrylate) copolymer. Typically, thecompositions have an inherent viscosity greater than about 0.2 dL/g,sometimes greater than about 0.5 dL/g, comprising polymerized primarymonomers and optional polar comonomer. Polar monomers suitable for usein accordance with this invention include those having hydroxyl, amide,or carboxylic, sulfonic, or phosphonic acid functionality.Representative examples include acrylamide, methacrylamide,N-vinyl-2-pyrrolidone, 2-hydroxyethylacrylate,2-hydroxyethylmethacrylate, hydroxypropylacrylate, acrylic acid,methacrylic acid, pyrrolidonyl ethyl acrylate, and alkoxyethylacrylates, such as 2-carboxyethylacrylate. In some embodiments, theamount by weight of polar monomer will not exceed about 40% of the totalweight of all monomers in order to avoid excessive firmness of the finalPSA product. Typically, polar monomer is incorporated to the extent ofabout 1% to about 20% by weight. In one embodiment the polar monomer isacrylamide.

In some embodiments, the copolymer can comprise the reaction product ofprimary and polar monomers and additional optional monomers which, whenpresent, are included in the polymerization reaction in quantities thatwill not render the PSA composition non-tacky. The optional additionalmonomers may be added, for example, to improve performance, reduce cost,or for other purposes. Examples of such optional monomers include vinylesters, such as vinyl acetate, vinyl chloride, vinylidene chloride,styrene, and macromonomers copolymerizable with the other monomers.Suitable macromonomers include polymethylmethacrylate,styrene/acrylonitrile copolymer, polyether, and polystyrenemacromonomers. Examples of useful macromonomers and their preparationare described in U.S. Pat. No. 4,693,776 (Krampe et al.), the disclosureof which is incorporated herein by reference

The copolymerization of the primary and polar monomers is accomplishedby conventional free radical solution polymerization. Monomers are firstdissolved in an organic solvent and subsequently polymerized utilizing asuitable free radical initiator which can be either thermally orphotochemically activated. Suitable thermally activated initiatorsinclude azo compounds such as 2,2′-azobis(isobutyronitrile) andperoxides such as benzoyl peroxide. Suitable photochemically activatedinitiators include benzoin ethyl ether and 2,2-dimethoxy-2-phenylacetophenone, for example. The amount of initiator present in thereaction mixture will generally be within the range from about 0.01% toabout 5% by weight of the total polymerizable composition.

The organic solvent used in the free radical copolymerization of theadhesive polymer can be any organic liquid that is inert to thereactants and product and which will not otherwise adversely affect thereaction. Suitable solvents include, without limitation, ethyl acetateas well as mixtures of solvents such as ethyl acetate combined withvarying amounts of toluene, isopropanol, methanol and the like. Theamount of solvent used will generally comprise about 30 to 70% by weightof the total weight of all reactants and solvent.

Polymerization of primary and polar monomers is accomplished with theconversion of the monomers to provide an initial reaction productgenerally comprising an acrylate (or methacrylate) copolymer. Thispolymerization is referred to herein as the “main” polymerizationreaction which may generally be accomplished within about 24 hours orless. While polymerization may be substantially completed within theforegoing time, non-polymerized impurities remain in the initialreaction product along with the desired polymer. Impurities willtypically include unreacted polymerizable materials such as residualprimary monomer(s) which are generally present in the initial reactionproduct at levels ranging from about 1% to 5%, as determined by gaschromatography, based upon the weight of the initial monomer charge.Impurities may also be present in the initial reaction product due tothe presence of non-polymerizable materials in the main polymerizationreaction. Non-polymerizable materials in the reaction product maycomprise decomposed initiator material, inhibitors, raw materialimpurities, and other agents that generally do not react or becomeincorporated into the adhesive polymer.

The method of the present invention provides purification steps toreduce the level of impurities in the final adhesive polymer. Thepresent method includes the addition of an oxidizing agent and areducing agent to the initial reaction product to initiate a furtherpolymerization of the unreacted monomers. Optionally, at least oneprecipitation step may also be included in the method. Thepolymerization of unreacted monomer and the precipitation step areeffective in reducing the levels of both the polymerizable material(e.g., residual monomer) and the non-polymerizable materials in theinitial reaction product to thereby provide a purified acrylate polymer.

As mentioned, the step of adding oxidizing agent and reducing agent tothe initial reaction product is performed to reduce the level ofpolymerizable material present in the initial reaction product followingthe main polymerization reaction. The initial reaction product obtainedfrom the main polymerization reaction will comprise the acrylatepolymer, unreacted polymerizable material and non-polymerizablematerial, all of which are dissolved in a suitable solvent. Theoxidizing agent and the reducing agent are selected to react with oneanother to generate a free radical capable of initiating furtherpolymerization of the unreacted monomers and other polymerizablematerial present in the initial reaction product. The resulting polymerformed following the addition of the oxidizing agent and the reducingagent is typically the same polymer generated during the mainpolymerization reaction, i.e., it is formed from the same types ofmonomers and the amount of side reactions leading to other types ofpolymers or compounds is minimal. The step of adding oxidizing agent,adding reducing agent, and allowing the unreacted polymerizable reactantin the initial reaction product to further react, thereby providing asecond reaction product comprising additional polymer is also referredto herein as a “purification reaction step.” Suitable oxidizing agentsinclude alkyl hydroperoxides, such as tertiary amyl hydroperoxide (TAHP)and tertiary butyl hydroperoxide (TBHP). Suitable reducing agentsinclude alkylamines, Vitamin C and sodium formaldehydesulfoxide (SFS).An optional promoter may be included to aid in the subsequent reaction.Suitable promoters include transition metal salts such as vanadylsulfate (VOSO₄) and ferrous sulfate (FeSO₄). Combinations of one or moreoxidizing agent may be used in conjunction with combinations of one ormore reducing agent and optionally in conjunction with one or morepromoters. Although not wishing to be bound by theory, it is believedthat a reaction occurs between the oxidizing agent and the reducingagent to generate a powerful free radical capable of reacting theremaining polymerizable material to a level beyond that achieved duringthe conventional free radical polymerization of the main polymerizationreaction.

Following the completion of the main polymerization reaction, one ormore doses of oxidizing agent and reducing agent may be added to thereactor, often with heating, and the resulting polymerization reactionis normally allowed to continue for an additional time period. In someembodiments, the reaction is allowed to run for as long as 24 hours. Inother embodiments, the reaction will be allowed to run for an additional6 hours. In general, a 6-24 hour reaction time has been found to besufficient for the acrylate polymers described herein. The free radicalsgenerated by the reaction of the additional oxidizing and reducingagents are typically reactive enough to reduce residual monomers levelsbelow 500 ppm. In some embodiments, the residual monomers will bereduced to levels below 100 ppm, often to levels below 50 ppm, andsometimes to levels below 10 ppm. In some embodiments, the oxidizingagents and reducing agents will be sufficiently decomposed followingtheir use in driving additional polymerization so that they will leavelittle or no undesirable material in the polymer solution.

It will be appreciated that the present invention encompasses processesthat includes a single purification reaction step (e.g., a singleaddition of oxidizing agent and a single addition of reducing agent) aswell as multiple purification reaction steps (e.g., two or more stepsadding oxidizing agent and reducing agent). It will be appreciated thatthe oxidizing agents and/or reducing agents used in any purificationreaction step may be the same as or different from other purificationreaction steps. The purification reaction step(s) facilitates additionalpolymerization of polymerizable material to provide a second reactionproduct comprising the polymer, remaining unreacted monomer, if any, andnon-polymerizable materials, all in solution in an appropriate solvent.

In some embodiments for performing the purification reaction step,oxidizing agent and reducing agent are separately dissolved in suitablesolvents to provide separate stock solutions of the oxidizing agent andreducing agent. Each of the stock solutions may be added to the initialreaction product to initiate further polymerization. In someembodiments, only one of the oxidizing agent or the reducing agent aredissolved in a suitable solvent to provide a stock solution that may beadded to the initial reaction product. The remaining oxidizing orreducing agent may then be added directly to the initial reactionproduct. In some embodiments, an optional promoter is dissolved in asuitable solvent to provide a stock solution that also may be added tothe initial reaction product.

In some embodiments, the oxidizing agent or oxidizing agent stocksolution is added to the initial reaction product and the mixture isblended until homogeneous prior to addition of the reducing agent orreducing agent stock solution. In some embodiments, the reducing agentor reducing agent stock solution is added to the initial reactionproduct and the mixture is blended until homogeneous and prior to theaddition of the oxidizing agent or oxidizing agent stock solution. Ingeneral, the oxidizing agent and the reducing agent are separately addedto the initial reaction product to maximize polymerization efficiency.The oxidizing agent will react with the reducing agent directly andgenerate radicals to initiate further polymerization of the unreactedmonomers. If no unreacted monomers remain in the initial reactionproduct, the radical created by reaction of the oxidizing agent and thereducing agent will be terminated without acting as initiators.

After the purification reaction step(s), the invention optionallyemploys one or more precipitation steps to precipitate the polymer outof its solvent so that the polymer may be separated from additionalunreacted monomer, if any, and from the non-polymerizable materialdissolved in the solvent. Precipitation is intended to further purifythe polymer and will typically follow the reaction purification step(s).One or more precipitation steps may be performed. In some embodiments,precipitation of the polymer is accomplished be varying the polarity ofthe solvent system in which the polymer is initially dissolved. Forexample, a copolymer of isooctyl acrylate/acrylamide (IOA/ACM) dissolvedin ethyl acetate can be precipitated by the addition of a suitableamount of methanol to alter the polarity of the solvent until thesolvent polarity is incompatible with that of the PSA polymer.

In some embodiments of the invention, two to three separate purificationreaction step(s) may be performed followed by two to three precipitationsteps to convert the original monomer to polymer and to remove thenon-polymerizable materials as well. Precipitation of the initialreaction product is not desirable, since the typical level of 1 to 5%unreacted polymerizable material remaining after a conventional freeradical polymerization is too high to be efficiently reduced byprecipitation. The inclusion of a precipitation step becomes moredesirable following one or more purification reaction steps where thelevel of residual unreacted polymerizable material is reduced below thatremaining after a conventional free radical polymerization. Thecombination of purification reaction and precipitation may reduce theremaining monomer content in the final polymer (e.g., followingpurification reaction and precipitation) to less than about 200 ppm,often less than about 100 ppm, and sometimes less than about 10 ppm.

The combination of purification reaction and precipitation is alsobelieved to reduce the remaining non-polymerizable material content inthe final polymer (e.g., following purification reaction andprecipitation) to less than about 200 ppm, often less than about 100ppm, and sometimes less than about 50 ppm.

The purified polymers obtained from the invention are generally suitablefor use in medical products which require adherence to human skin. Infact, the adhesives provided by the invention are generally suitable foruse in direct contact with human skin.

Following one or more purification reactions (with or without one ormore optional precipitation steps), the resultant acrylate (ormethacrylate) copolymer may be blended with optional components such ascompatible tackifying resins and/or plasticizers in order to optimizethe tack and peel properties of the resulting pressure-sensitiveadhesive (PSA) composition. Examples of useful tackifying resins includerosin, rosin derivatives, hydrogenated rosin derivatives, polyterpeneresins, phenolic resins, coumarone-indene resins, and the like.Plasticizers that can be employed include the well-known extender oils(aromatic, paraffinic, or naphthenic), as well as a wide variety ofliquid polymers. When used, tackifying resin is preferably added in anamount not to exceed about 150 parts by weight per 100 parts by weightcopolymer, and plasticizer may be added in an amount up to about 50parts by weight per 100 parts by weight copolymer.

Other optional components may be added to the adhesive formulationsprovided by the present invention. Exemplary of such additionalingredients include pigments, fillers, stabilizers, medicaments (alsoreferred to here as drugs), pharmaceutically acceptable materials thatmay be used as skin penetration enhancers (i.e., substances thatincrease the permeation rate of a drug across or into the skin) orsolubilizers (i.e., substances that effectively solubilize a drug) intransdermal drug delivery systems and various polymeric additives.

Exemplary drugs include any substance capable of local or systemiceffect when administered to the skin. In a preferred embodiment, thedrug will be capable of systemic effect when administered to the skin.Clonidine, estradiol, nicotine, nitroglycerine, scopolamine, andfentanyl, are examples of drugs commercially available in the form oftransdermal devices. Others include anti-inflammatory drugs, bothsteroidal (e.g., hydrocortisone, prednisolone, triamcinolone) andnonsteroidal (e.g., naproxen, piroxicam); bacteriostatic agents (e.g.,chlorhexidine, hexylresorcinol); antibacterials (e.g., penicillins suchas penicillin V, cephalosporins such as cephalexin, erythromycin,tetracycline, gentamycin, sulfathiazole, nitrofurantoin, and quinolonessuch as norfloxacin, flumequine, and ibafloxacin); antiprotozoals (e.g.,metronidazole); antifungals (e.g., nystatin); coronary vasodilators;calcium channel blockers (e.g., nifedipine, diltiazem); bronchodilators(e.g., theophylline, pirbuterol, salmeterol, isoproterenol); enzymeinhibitors such as collagenase inhibitors, protease inhibitors, elastaseinhibitors, lipoxygenase inhibitors (e.g., A64077), and angiotensinconverting enzyme inhibitors (e.g., captopril, lisinopril); otherantihypertensives (e.g., propranolol); leukotriene antagonists (e.g.,ICI204,219); anti-ulceratives such as H2 antagonists; steroidal hormones(e.g., progesterone, testosterone, estradiol); antivirals and/orimmunomodulators (e.g., 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine,1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, andacyclovir); local anesthetics (e.g., benzocaine, propofol); cardiotonics(e.g., digitalis, digoxin); antitussives (e.g., codeine,dextromethorphan); antihistamines (e.g., diphenhydramine,chlorpheniramine, terfenadine); narcotic analgesics (e.g., morphine,buprenorphine); peptide hormones (e.g., human or animal growth hormones,LHRH); cardioactive products such as atriopeptides; proteinaceousproducts (e.g., insulin); enzymes (e.g., anti-plaque enzymes, lysozyme,dextranase); antinauseants; anticonvulsants (e.g., carbamazine);immunosuppressives (e.g., cyclosporine); psychotherapeutics (e.g.,diazepam); sedatives (e.g., phenobarbital); anticoagulants (e.g.,heparin); analgesics (e.g., acetaminophen); antimigraine agents (e.g.,ergotamine, melatonin, sumatripan); antiarrhythmic agents (e.g.,flecainide); antiemetics (e.g., metaclopromide, ondansetron); anticanceragents (e.g., methotrexate); neurologic agents such as anxiolytic drugs;hemostatics; anti-obesity agents; and the like, as well aspharmaceutically acceptable salts and esters thereof. The amount of drugthat constitutes a therapeutically effective amount can be readilydetermined by those skilled in the art with due consideration of theparticular drug, the particular carrier, and the desired therapeuticeffect.

Exemplary skin penetration enhancers and/or solubilizers include C₈-C₂₀fatty acids such as isostearic acid, octanoic acid, and oleic acid;C₈-C₂₀ fatty alcohols such as oleyl alcohol and lauryl alcohol; loweralkyl esters of C₈-C₂₀ fatty acids such as ethyl oleate, isopropylmyristate, butyl stearate, and methyl laurate; di(lower) alkyl esters ofC₆-C₈ diacids such as diisopropyl adipate; monoglycerides of C₈-C₂₀fatty acids such as glyceryl monolaurate; tetraglycol(tetrahydrofurfuryl alcohol polyethylene glycol ether); tetraethyleneglycol (ethanol,2,2′-(oxybis(ethylenoxy))diglycol); C₆-C₂₀ alkylpyrrolidone carboxylates; polyethylene glycol; propylene glycol;2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether;N,N-dimethyldodecylamine-N-oxide and combinations of the foregoing.Alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethylethers, polyethylene oxide dimethyl ethers, glycerol, and N-methylpyrrolidone are also suitable. The terpenes are another useful class ofpharmaceutical excipients, including pinene, d-limonene, carene,terpineol, terpinen-4-ol, carveol, carvone, pulegone, piperitone,menthone, menthol, neomenthol, thymol, camphor, borneol, citral, ionone,and cineole, alone or in any combination.

In addition to adhesive compositions, coated sheet materials may also beprovided comprising a backing member and an adhesive coating, thecoating comprising the acrylate (or methacrylate) composition describedherein and covering at least a portion of one major surface of thebacking member. Specific products are provided that comprise such acoated sheet material such as, for example, rolls of tape, transfertapes, adhesive bandages, transdermal patches and the like. A roll oftape comprises a flexible backing sheet having at least one majorsurface coated with the adhesive described herein. The transfer tapecomprises a film of the adhesive composition on at least one releaseliner.

In some embodiments, the coated sheet materials are provided in the formof adhesive bandages. The adhesive bandages may comprise any of avariety of constructions wherein the bandage includes a backing materialwith the adhesive described herein coated on one of the major surfacesof the backing to facilitate ability of the bandage to adhere to humanskin. The adhesive described herein is generally suitable for use inwound dressings or bandages.

In some embodiments, the coated sheet materials are provided in the formof a transdermal patch suitable for the continuous transdermal deliveryof a therapeutically effective amount of an appropriate medicament.Suitable transdermal drug delivery devices include gelled or liquidreservoirs, such as in U.S. Pat. No. 4,834,979 (Gale), so-called“reservoir” patches; devices containing matrix reservoirs attached tothe skin by an adjacent adhesive layer, such as in U.S. Pat. No.6,004,578 (Lee, et al.), so-called “matrix” patches; and devicescontaining PSA reservoirs, such as in U.S. Pat. Nos. 6,365,178(Venkateshwaran et al.), 6,024,976 (Miranda et al.), 4,751,087 (Wick)and 6,149,935 (Chiang et al.), so-called “drug-in-adhesive” patches, thedisclosures of which are incorporated in their entirety herein byreference thereto.

In one embodiment, transdermal patches according to the inventioncomprise (a) a flexible backing; (b) the adhesive described hereincoated on at least one major surface of the flexible backing; and (c)nitroglycerin in an amount suitable for substantially continuoustransdermal delivery to a subject over a prolonged period in an amountwhich is therapeutically effective. The adhesive coating for thetransdermal patch may optionally comprise a skin penetration enhancersuch as a combination of (i) a fatty acid ester prepared from a fattyacid containing about 14 to 20 carbon atoms and an alkyl alcoholcontaining 2 to about 6 carbon atoms and a single hydroxyl, and (ii)glyceryl monolaurate, the fatty acid ester being present in an amount byweight of about 1 to 30 percent of the total weight of the adhesivecoating, and glyceryl monolaurate being present in an amount by weightof about 0.2 to 5 percent of the total weight of the adhesive coating.When such a skin penetration enhancing combination is employed, thenitroglycerin content in the adhesive coating may be about 10 to 45percent by weight of the total weight of the adhesive coating.

The adhesive compositions according to the present invention are easilycoated upon suitable flexible or inflexible backing materials byconventional coating techniques to produce Pressure sensitive adhesive(PSA) coated sheet materials. The flexible backing may be of anymaterial which may be utilized as a tape or a backing appropriate foradhesive backing or may be of any other flexible material.Representative examples of flexible tape backing materials includepaper, plastic films such as poly(propylene), poly(ethylene), poly(vinylchloride), polyester e.g., poly(ethylene terephthalate), celluloseacetate, and ethyl cellulose. Backings may also be of woven fabricformed of threads of synthetic or natural materials such as cotton,nylon, rayon, glass, or ceramic material, or they may be of a nonwovenfabric such as air-laid webs of natural or synthetic fibers or blends ofthese. In addition, the backing may be formed of metal, metallizedpolymeric film, or ceramic sheet material. The PSA composition may alsobe coated as films on a suitable release liner to provide an adhesivetransfer film.

The PSA compositions provided by the present invention may be coatedonto a surface by any of a variety of conventional coating techniquessuch as roll coating, knife coating, or curtain coating. Primers may beused, but they are not always necessary. The resultant coatings do notrequire curing or crosslinking. However, if enhancement of resistance tosolvents, etc., is desired, crosslinking may be effected by standardmethods well-known in the art, such as radiation curing (electron beamor ultraviolet light) or chemical crosslinking.

EXAMPLES Test Methods

Residual N,N-dimethylaminoethyl acrylate dimethyl sulfate quaternary(DMAEAMS) and methoxylated poly(ethylene glycol) acrylate (AM-90G fromSan Esters) were measured by high performance liquid chromatography(HPLC) using an Agilent LC-MSD with MS detector, column: HamiltonPRP-1,5 μm, 150×2.1 mm. Standards of the two monomers were made in 50/50water/acetonitrile with concentration ranging from 100 to 0.1 μg/mL. Thestandards were analyzed and calibration curves for each of the standardswere made from a second order polynomial fit of peak area versusconcentration. Residual DMAEAMS and the methoxylated poly(ethyleneglycol) acrylate were reported as ppm based on dry polymer weight.

Residual acrylamide (ACM) was measured by gas chromatography (GC) usingan HP 6890 Plus gas chromatograph with a Flame Ionization Detector(FID), an HP 7683A automatic sampler, and a 30 m HP-Innowax capillarycolumn. Standards were prepared between 10 ppm (w/v) and 10 ppb (w/v) inethyl acetate spiked with an internal standard of 500 ppb (w/v)1-methyl-2-pyrrolidinone (NMP). The samples were dissolved and dilutedto 10% (w/v) in ethyl acetate spiked with 500 ppb (w/v) NMP. Residualacrylamide is reported as ppm based on dry polymer weight.

Residual isooctyl acrylate (IOA) was measured by gas chromatography (GC)using an HP 6890 Plus gas chromatograph with a Flame Ionization Detector(FID), an HP 7683A automatic sampler, and a 105 m Rtx-1701 capillarycolumn. Standards were prepared between 100 ppm (w/v) and 100 ppb (w/v)in ethyl acetate spiked with an internal standard of 5 ppm (w/v) butylacrylate (BA). The samples were dissolved and diluted to 10% (w/v) inethyl acetate spiked with 5 ppm (w/v) BA.

Initial Reaction Product A1-A4

Four initial reaction products were prepared and designated A1, A2, A3,and A4. The products were pressure-sensitive adhesive copolymersolutions prepared from isooctyl acrylate and acrylamide (93:7)according to the general methods described in Examples 5 and 6 of U.S.Pat. No. 4,751,087. The resulting copolymer solutions were 23% solids ina 90:10 blend of ethyl acetate and methanol. The inherent viscosity (IV)of each copolymer solution was 1.32 dL/g. Inherent viscosity wasmeasured for a concentration of 0.15 g/dL in ethyl acetate at 27° C.

An aliquot of each polymer solution A1- A4 was tested by gaschromatography (GC) and the residual acrylamide level was obtained. Theresidual ACM and IV are shown in Table 1.

TABLE 1 Copolymer Solution IV [dL/g] Residual ACM [ppm] A1 1.32 2029 A21.35 1480 A3 1.39 1644 A4 1.39 1953

Initial Reaction Product B

An initial reaction product comprising a pressure-sensitive adhesivecopolymer solution was prepared by mixing together 2-ethylhexyl acrylate(420 g), N,N-dimethylaminoethyl acrylate dimethyl sulfate quaternary(150 g solution, 80% in water, available as Ageflex FA1Q80DMS fromCiba), methoxylated poly(ethylene glycol) acrylate (60 g, available asAM-90G from San Esters), acetone (502 g), methanol (200 g) and2,2′-azobis(2-methylbutanenitrile) (1.50 g) (commercially available fromDu Pont under the trade designation VAZO-67). The resulting homogeneoussolution was divided into four bottles at 333 g each. The bottles werepurged with nitrogen, sealed, and heated in a water bath at 58° C. for16 hours. The inherent viscosity of the resultant polymer solution was0.43 dL/g. Inherent viscosity was measured for a concentration of 0.50g/dL in tetrahydrofuran at 27° C.

Stock Solutions

Stock solutions of the following oxidizing agents, reducing agents, andpromoters were prepared for use in the following examples.

TAHP: A 5% solids solution of tertiary amyl hydroperoxide was preparedby mixing a solution of 85% TAHP in water (5.88 g, available from AkzoNobel) with methanol (94.12 g).VOSO₄: A 0.5% solids solution of vanadyl sulfate hydrate (VOSO₄-3H₂Osolution) was prepared by adding VOSO₄-3H₂O (0.50 g) to water (99.5 g).Vitamin C: A 5% solids solution of vitamin C was prepared by addingvitamin C (5.0 g) to methanol (95.0 g).TBHP: A 5% solids solution of tertiary butyl hydroperoxide was preparedby mixing a solution of 70% TBHP in water (7.14 g, available from AkzoNobel) with ethanol (92.86 g).SFS: A 5% solids solution of sodium formaldehydesulfoxide was preparedby adding sodium formaldehydesulfoxide (5.0 g) to water (95.0 g).FeSO₄: A 0.50% solids solution of ferrous sulfate was prepared by addingferrous sulfate (0.50 g) to water (99.5 g).

Example 1

Step 1: An aliquot of initial reaction product (Initial reaction productA2, 543.5 g solution, 125 g solids) was added to a 1-quart (0.95 L)amber glass bottle. To this solution was added TAHP solution (2.50 gsolution, 0.125 g solids) and VOSO₄ solution (0.50 g solution, 0.0025 gsolids). The bottle was closed and mixed for 10 minutes. Vitamin Csolution (2.50 g solution, 0.125 g solids) was added to the bottlefollowed by a nitrogen purge to remove all of the oxygen. The bottle wassealed and heated in a water bath at 60° C. for 2 hours. It was allowedto cool down to ambient temperature.Step 2: The bottle was unsealed and additional TAHP solution (2.50 gsolution, 0.125 g solids) was added. The bottle was closed and mixed for10 minutes. Additional Vitamin C solution (2.50 g solution, 0.125 gsolids) was added to the bottle followed by a nitrogen purge to removeall of the oxygen. The bottle was then sealed and heated in a water bathat 60° C. for 2 hours. It was allowed to cool down to ambienttemperature.Step 3: The bottle was unsealed and additional TAHP solution (2.50 gsolution, 0.125 g solids) was added. The bottle was closed and mixed for10 minutes. Additional Vitamin C solution (3.75 g solution, 0.188 gsolids) was added to the bottle followed by a nitrogen purge to removeall of the oxygen. The bottle was then sealed and heated in a water bathat 60° C. for 2 hours. It was allowed to cool down to ambienttemperature.Step 4: The bottle was unsealed and additional TAHP solution (2.50 gsolution, 0.125 g solids) was added. The bottle was closed and mixed for10 minutes. Additional Vitamin C solution (3.75 g solution, 0.188 gsolids) was added to the bottle followed by a nitrogen purge to removeall of the oxygen. The bottle was then sealed and heated in a water bathat 60° C. for 24 hours. It was allowed to cool down to ambienttemperature.

Residual acrylamide of the purified solution was measured by gaschromatography as being described above. (The amount of residualacrylamide was below the detection limit of 5 ppm. The total amount ofoxidizing agents and reducing agents added (in ppm) and the totalpurification reaction time is shown in Table 2.

Examples 2 to 12

Aliquots of initial reaction products A1-A4 were treated as described inExample 1 with the following exceptions: some examples involved 3reaction steps instead of 4, SFS was used in place of vitamin C in someexamples, FeSO₄ was used in place of or in combination with VOSO₄. Thetotal amount of oxidizing agents and reducing agents added (in ppm) andthe total purification reaction time at each step is shown in Table 2.

TABLE 2 Initial Vitamin Reaction Residual Ex. Step reaction TAHP C SFSVOSO₄ FeSO₄ time ACM, No. No. product [ppm] [ppm] [ppm] [ppm] [ppm] [hr][ppm]* 1 1 Example 1000 1000 — 20 — 2 2 A2 1000 1000 — — — 2 3 1000 1500— — — 2 4 1000 1500 — — — 18 N/D 2 1 Example 1000 1000 — 20 — 2 2 A11000 1000 — — — 2 3 1000 — 1000 — — 12 N/D 3 1 Example 1000 1000 — 20 —2 2 A2 1000 1000 — — — 2 3 1000 — — — — 26 1000 — — 17 4 1 Example 10001000 — 50 — 2 27 2 A2 1000 1000 — — — 2 3 1000 — 1000 — — 32 5 1 Example1000 1000 — 50 — 2 2 A2 1000 1000 — — — 2 3 1000 — 1000 — — 22 N/D 6 1Example 1000 1000 — 50 — 2 2 A2 1000 1000 — — — 2 3 1000 1000 — — — 2N/D 4 1000 — 1000 — — 24 7 1 Example 1000 1000 — 50 50 2 2 A2 1000 1000— — — 2 3 1000 1000 — — — 2 N/D 4 1000 — 1000 — — 24 8 1 Example 10001000 — 20 — 2 2 A3 1000 1000 — — — 2 3 1000 1500 — — — 2 N/D 4 1000 1500— — — 24 9 1 Example 1000 1000 — 20 — 2 2 A3 1000 1000 — — — 2 3 10001500 — — — 2 N/D 4 1000 1500 — — — 6 10 1 Example 1000 1000 — 20 — 2 N/D2 A3 1000 1000 — — — 2 3 1000 1500 — — — 8 11 1 Example 1000 1000 — 20 —2 N/D 2 A4 1000 1000 — — — 2 3 1000 1500 — — — 2 4 1000 1500 — — — 6 121 Example 1000 1000 — 20 — 2 N/D 2 A4 1000 1000 — — — 2 3 1000 1500 — —— 8 *N/D - below detection limit of 5 ppm

Example 13

Precipitation cycle 1: To an aliquot of the purified initial reactionproduct (Example 4, 203 g solution, 46.7 g solids, residual IOA: 550,ACM: 27 ppm based on dry polymer weight) was added methanol (100 g) toprecipitate the polymer. This mixture was shaken at ambient temperaturefor 3 hours to ensure that residual monomers reached equilibrium betweenthe solvent and the precipitated polymer phase. The solvent phase (165g) was then phase separated from the precipitated polymer. To thepolymer was added ethyl acetate (65 g) to redissolve the polymer into aclear solution.Precipitation cycle 2: To this solution was added another dose ofmethanol (100 g) to precipitate the polymer, followed by shaking foranother 3 hours to wash the precipitated polymer. Solvents (163 g) wereseparated from the polymer. Ethyl acetate (63 g) was added to redissolvethe polymer into the clear solution. This sample was analyzed forresidual IOA and ACM by GC. Residual IOA and ACM results, both beforeand after precipitation, are shown below in Table 3. Results aresummarized in Table 3.

Example 14-16

Samples were prepared using the same procedures as described above inExample 13 with the exception that the starting purified initialreaction product was varied and three precipitation cycles wereperformed. The starting purified initial reaction product, number ofprecipitation cycles, and residual IOA and ACM, both before and afterprecipitation, are shown below in Table 3.

TABLE 3 Residual Residual Starting purified IOA/ACM Before Precip-IOA/ACM After Ex. initial reaction Precipitation itation PrecipitationNo. product [ppm] Cycles [ppm] 13 Example 4 550/27 2 160/ND  14 Example8 503/ND 3 46/ND 15 Example 9 384/ND 3 44/ND 16 Example 10 392/ND 380/ND *N/D - below detection limit of 5 ppm

Example 17

An aliquot of initial reaction product B (333 g, 150 g solids) was addedto a 1-quart (0.95 L) amber glass bottle. To this solution was addedTBHP solution (3.0 g solution, 0.15 g solids). The bottle was mixed atambient temperature for 20 min to ensure that it was homogeneous. SFSsolution (3.0 g solution, 0.15 g solids) was added to the bottlefollowed by a nitrogen purge to remove all of the oxygen. The bottle wassealed and heated in a water bath at 60° C. for 2 hours. It was allowedto cool down to ambient temperature.

The bottle was unsealed and additional TBHP solution (3.0 g solution,0.15 g solids) was added. The bottle was mixed at ambient temperaturefor 20 min. Additional SFS solution (3.0 g solution, 0.15 g solids) wasadded to the bottle followed by a nitrogen purge to remove all of theoxygen. The bottle was sealed and heated in a water bath at 60° C. for 2hours.

Residual DMAEAMS and AM-90G were measured by HPLC at 90 ppm and 330 ppm,respectively.

An aliquot of untreated copolymer B solution was tested by HPLC andresidual DMAEAMS and AM-90G were 3500 ppm and 2900 ppm, respectively.

Example 18

A pressure-sensitive adhesive copolymer solution was prepared by addingbutyl acrylate (18.0 g), DMAEAMS (2.5 g, 80% in water), acetone (26 g),methanol (20 g) and VAZO-67 (0.06 g) to a 4-oz glass bottle and mixinguntil homogeneous. The bottle was purged with nitrogen, sealed andheated at 57° C. for 24 hours. The resultant copolymer solution wasdiluted to 30% solids by addition of a 1.3:1 mixture of acetone/methanol(8.0 g).

A TAHP solution (1000 ppm, 0.36 g solution, 0.018 g solids) was added tothe copolymer solution and mixed for 10 minutes. Vitamin C solution(0.36 g solution, 0.018 g solids) and 2 drops of a 1% aqueous VOSO₄solution were added to the bottle followed by a nitrogen purge to removeall of the oxygen. The bottle was sealed and heated in a water bath at57° C. for 2 hours. It was allowed to cool down to ambient temperature.

Additional TAHP solution (1000 ppm, 0.36 g solution, 0.018 g solids) wasadded to the copolymer solution and mixed for 10 minutes. Additionalvitamin C solution (1000 ppm, 0.36 g solution, 0.018 g solids) was addedto the bottle followed by a nitrogen purge to remove all of the oxygen.The bottle was sealed and heated in a water bath at 57° C. for 2 hours.

Additional TAHP solution (800 ppm, 0.29 g solution, 0.0144 g solids) wasadded to the copolymer solution and mixed for 10 minutes. Additionalvitamin C solution (800 ppm, 0.29 g solution, 0.0144 g solids) was addedto the bottle followed by a nitrogen purge to remove all of the oxygen.The bottle was sealed and heated in a water bath at 57° C. for 2 hours.

Residual DMAEAMS was measured by HPLC at 259 ppm.

1. A method for the manufacture of an adhesive, comprising: (A)Providing an initial reaction product of a solution polymerizationreaction, the initial reaction product comprising polymer, unreactedpolymerizable reactant, non-polymerizable material, and solvent; and (B)Purifying the initial reaction product by adding an oxidizing agent anda reducing agent to the initial reaction product and allowing theunreacted polymerizable reactant in the initial reaction product tofurther react, thereby providing a second reaction product comprisingadditional polymer and a lower level of unreacted polymerizable reactantthan was present in the initial reaction product.
 2. The method asdefined in claim 1 wherein step (A) of providing an initial reactionproduct of a solution polymerization reaction comprises polymerizing aprimary acrylate monomer comprising a C₄ to C₁₂ alkyl acrylate.
 3. Themethod as defined in claim 1 wherein step (A) of providing an initialreaction product of a solution polymerization reaction comprisespolymerizing a primary acrylate monomer comprising an alkyl acrylate anda polar monomer.
 4. The method as defined in claim 3 wherein the primaryacrylate monomer is selected from the group consisting of isooctylacrylate, 2-ethylhexyl acrylate, 2-methyl butyl acrylate, butyl acrylateand combinations of two or more of the foregoing.
 5. The method asdefined in claim 4 wherein the polar monomer is selected from the groupconsisting of acrylamide, methacrylamide, N-vinyl-2-pyrrolidone,2-hydroxyethylacrylate, hydroxypropylacrylate, acrylic acid, methacrylicacid, pyrrolidonyl ethyl acrylate, 2-carboxyethylacrylate, andcombinations of two or more of the foregoing.
 6. The method as definedin claim 1 wherein a free radical is generated by reaction of theoxidizing agent with the reducing agent.
 7. The method as defined inclaim 1 wherein the oxidizing agent is an alkyl hydroperoxide selectedfrom the group consisting of tertiary amyl hydroperoxide, tertiary butylhydroperoxide and combinations of two or more of the foregoing.
 8. Themethod as defined in claim 1 wherein the reducing agent is selected fromthe group consisting of alkylamines, sodium formaldehydesulfoxide,Vitamin C and combinations of two or more of the foregoing.
 9. Themethod as defined in claim 1 wherein step (B) of purifying the initialreaction product further comprises adding a promoter to the initialreaction product.
 10. The method as defined in claim 9 wherein thepromoter comprises a transition metal salt selected from the groupconsisting of vanadyl sulfate hydrate, ferrous sulfate and combinationsof two or more of the foregoing.
 11. The method as defined in claim 1wherein the second reaction product comprises a level of unreactedpolymerizable reactant of less than about 500 ppm.
 12. The method asdefined in claim 1 wherein the second reaction product comprises a levelof unreacted polymerizable reactant of less than about 100 ppm.
 13. Themethod as defined in claim 1, further comprising the steps ofPrecipitating the polymer from the second reaction product to provide aprecipitated polymer; and Separating the precipitated polymer from theremainder of the second reaction product, the precipitated polymercomprising a lower level of non-polymerizable material or unreactedpolymerizable reactant or both non-polymerizable material and unreactedpolymerizable reactant than was present in the second reaction product.14. The method as defined in claim 13 wherein precipitating the polymerfrom the second reaction product comprises modifying the polarity of thesolvent until the polymer is no longer soluble therein.
 15. The methodas defined in claim 13 wherein the precipitated polymer comprises alevel of unreacted polymerizable reactant of less than about 500 ppm.16. The method as defined in claim 13 wherein the precipitated polymercomprises a level of unreacted polymerizable reactant of less than about100 ppm.
 17. A method for the manufacture of an adhesive, comprising:(A) Providing an initial reaction product of a solution polymerizationreaction, the initial reaction product comprising a copolymer ofisooctyl acrylate and acrylamide, unreacted polymerizable reactant,non-polymerizable material, and solvent; (B) Purifying the initialreaction product by adding an oxidizing agent and a reducing agent tothe initial reaction product and allowing the unreacted polymerizablereactant in the initial reaction product to further react, therebyproviding a second reaction product comprising additional polymer and alower level of unreacted polymerizable reactant than was present in theinitial reaction product; and (C) Precipitating the non-polymerizablematerial from the reaction product to provide a purified copolymer ofisooctyl acrylate and acrylamide comprising less than about 200 ppm ofunreacted isooctyl acrylate or acrylamide.